The potentiating effects of hyperthermia on various forms of chemotherapy is well established preclinically. Alkylating agents are one class of genotoxic drugs in which cytotoxicity appears to increase linearly with increasing temperature. In this regard, we demonstrated a dose (or thermal) enhancement ratio of 3.6 when L929 cells were treated with melphalan (L-PAM) and 41-degree-celsius (C) hyperthermia. It is noteworthy that such heat/L-PAM interactions can also extrapolate to a therapeutic gain in the context of animal studies. From a clinical standpoint, studies involving hyperthermic limb perfusion and L-PAM for local/regional disease have shown prolonged survival and disease free survival both in randomized and non-randomized trials involving melanoma patients. Cavaliere's group at the Instituto Regina Elena in Rome observed a two-fold increase in the complete response rate if limb perfusions were performed at ~41.8C, as opposed to 41C, at two doses of melphalan. Their data suggested a significant (P=0.02) improvement in clinical response due to L-PAM with increasing temperature, which is concordant with our in vitro results. Patients with metastatic malignant melanoma are generally refractory to standard therapy. Thus, in order to extend the aforementioned laboratory and clinical results to systemic treatment of cancer patients, a phase I study of 41.8C whole body hyperthermia (WBH) coupled with increasing doses of L-PAM was initiated at the University of Wisconsin. A new delivery system, i.e., the Aquatherm, was used for administration of WBH. The results of this study demonstrated that the pharmacokinetics of L-PAM were not altered by WBH (i.e., clearance, elimination half life and volume or distribution). The phase II dose of L-PAM plus WBH was established at 17.5 mg/m2. In the context of the study five patients with malignant melanoma were treated. Responses observed included: two patients with partial remission; two patients with improvement; and one patient with progressive disease. These data taken collectively strongly support the initiation of a phase II trial of WBH and L-PAM for patients with metastatic malignant melanoma.